The Clinical Molecular Profiling Core's (CMPC) technology development efforts are directed at expanding the number of clinical samples which can be analyzed and improving next-generation sequencing technologies. Despite the best intentions of clinical researchers, accrual of appropriate biospecimen remains the most challenging aspect of implementing the CMPC's precision medicine mission. For this reason, we have directed efforts to the problem of analyzing formalin fixed paraffin embedded (FFPE) specimens. The ability to use FFPE is extremely attractive since this specimen type fits into routine pathology laboratory practices. An example of a project in this area is provided by our study of DNA methylation in cancer. Using a novel microarray based platform, we have established that it is possible to profile sites of DNA methylation in FFPE specimens as accurately as in frozen specimens. This will open up large archives of tissue specimens to this type of research. To complement this tumor specimen type, we regularly use saliva specimens to provide germline DNA to better identify somatic mutations in the cancer specimens. As expected, DNA based assays are relatively robust, however, RNA is a much more labile template. We have explored the possibility of obtaining mRNA signatures from archival material such as FFPE. This is difficult because although the platform technology is not intrinsically limiting, the fragmented RNA found in such compromised samples are subject to many variables in sample processing prior to stabilization (warm ischemia time, processing time, processing chemistry etc.) and after stabilization to varying degrees of time and conditions of storage. In addition to this, we have published in the literature on stabilizing extracted RNA for downstream microarray use in Stevenson et al. (2015), Long-term stability of total RNA in RNAstable as evaluated by expression microarray. To help ensure reproducibility and provide for quality results, we have developed refined standard operating procedures for extracting nucleic acid from clinical specimens. We have successfully extracted DNA from FFPE samples for use in methylation assays; significantly, these samples have been very suitable for comparative genomic hybridization and DNA sequencing. We have developed a protocol for extracting DNA from cytology slides and have been able to generate remarkably high quality DNA copy number and mutation profiles from this material. Organic solvents such as phenol and chloroform have been used for decades to purify nucleic acids from blood and tissues. However, the use and waste produced with these chemicals creates health hazard issues and problems of disposal. Therefore, we have investigated and validated new protocols for extraction of DNA, RNA, and microRNA from both research and clinical specimens without the use of organic solvents. These efforts are illustrative of our commitment to extend the utility of genome profiling technologies to realistically obtainable clinical samples. An important new area of technology development is in the application of next-generation sequencing technologies and development of protocols especially in library construction for use with clinical specimens. These new technologies offer the possibility of generating genomic profiling data on tumor specimens in a much deeper and more robust way than has been possible with microarrays. For example, it may become possible to profile large numbers of drug targets for mutations which may promote tumor growth, data which could be incorporated into future clinical trials design. Efforts are ongoing to adapt commercial protocols to the reality of testing human specimens; in one (Chaisaingmongkol et al., 2017) we discovered that changing the blockers had a profound effect on the depth of coverage.